DACLASTAVIR
ELBASAVIR+ GRAZOPREVIR
LEDIPASVIR + SOFOSBUVIR
PARITAVPREVIR + RITONAVIR + OMBITASVIR + DASABUVIR
RIBAVIRIN
SOFOSBUVIR
SIMEPREVIR
- Cytochrome P450 enzyme substrate: CYP3A4
- Action to be taken: Potential dose reduction. Caution with close monitoring.
- Rationale: The dose of daclatasvir must be reduced to 30 mg once daily when administered in combination with strong CYP3A4 inhibitors, such as grapefruit juice. In vitro studies have shown that cannabis is metabolized by CYP450 enzymes, mainly by CYP3A4 and CYP2C19. Furthermore, various in vitro studies have found cannabinoids to be weak inhibitors of CYP enzymes. However one study showed that CBD is a potent inhibitor of CYP3A4. Taking these drugs together may increase daclatasvir serum concentrations, thus, increasing the risk for adverse effects.
ELBASAVIR+ GRAZOPREVIR
- Cytochrome P450 enzyme substrate: CYP3A4
- Action to be taken: Avoid if possible
- Rationale: Elbasvir metabolism can be inhibited by CYP3A inhibitors, such as grapefruit juice. In vitro studies have shown that cannabis is metabolized by CYP450 enzymes, mainly by CYP3A4 and CYP2C19. Furthermore, various in vitro studies have found cannabinoids to be weak inhibitors of CYP enzymes. However one study showed that CBD is a potent inhibitor of CYP3A4. Concomitant administration may result in increased plasma concentrations of elbasvir and grazoprevir, which may result in adverse effects, such as elevated ALT concentrations and hepatotoxicity.
LEDIPASVIR + SOFOSBUVIR
- P-gp substrate
- Action to be taken: No action needed
- Rationale:In vitro, no detectable metabolism of ledipasvir was observed by human CYP1A2,CYP2C8, CYP2C9, CYP 2C19, CYP2D6, and CYP3A4.Ledipasvir and sofosbuvir are substrates of drug transporters P-gp and BCRP while GS-331007 is not. In vitro study has shown that CBD is a potent inhbitor of P-gp mediated drug transport. Coadministration with drugs that inhibit P-gp and/or BCRP may increase ledipasvir and sofosbuvir plasma concentrations without increasing GS-331007 plasma concentration; HARVONI may be coadministered with P-gp and/or BCRP inhibitors.
PARITAVPREVIR + RITONAVIR + OMBITASVIR + DASABUVIR
- Cytochrome P450 enzyme substrate: CYP3A4
- P-gp substrate
- Action to be taken: Caution with close monitoring
- Rationale: Administration of dasabuvir, ombitasvir, paritaprevir, and ritonavir with grapefruit juice can result in elevated concentrations of all 4 antivirals. Similar to grapefruit juice, cannabis can inhibit both P-gp and CYP3A4. Caution and close monitoring is advised.
RIBAVIRIN
- Action to be taken: No action needed
- Rationale:Results of in vitro studies using both human and rat liver microsome preparations indicated little or no cytochrome P-450 enzyme-mediated metabolism of ribavirin, with minimal potential for P-450 enzyme based drug interactions. In vitro studies indicate that ribavirin does not inhibit CYP 2C9, CYP 2C19, CYP 2D6 or CYP 3A4. Therefore based on available data interactio of ribavirin and cannabis is unlikely.
SOFOSBUVIR
- Action to be taken: No action needed
- Rationale:Sofosbuvir is a substrate of drug transporter P-gp and breast cancer resistance protein (BCRP).In vitro study has shown that CBD is a potent inhbitor of P-gp mediated drug transport. Coadministration of SOVALDI with drugs that inhibit P-gp and/or BCRP may increase sofosbuvir plasma concentration without increasing GS-331007 plasma concentration; accordingly, SOVALDI may be coadministered with P-gp and/or BCRP inhibitors.
SIMEPREVIR
- Cytochrome P450 enzyme substrate: CYP3A4
- Action to be taken: Avoid if possible. Potential adverse effects
- Rationale: Simeprevir is metabolized by CYP3A4 isoenzyme. In vitro studies have shown that cannabis is metabolized by CYP450 enzymes, mainly by CYP3A4 and CYP2C19. Furthermore, various in vitro studies have found cannabinoids to be weak inhibitors of CYP enzymes. However other studies have shown that CBD is a potent inhibitor of CYP3A4 and CYP2C19 .The FDA-labeling states that co-administration with moderate or strong CYP3A4 inhibitors is not recommended as this may lead to significantly higher simeprevir exposure, which may result in adverse effects.
References
- Watanabe K, Yamaori S, Funahashi T, et al. Cytochrome P450 enzymes involved in the metabolism of tetrahydrocannabinols and cannabinol by human hepatic microsomes. Life Sci. 2007;80:1415-1419.
- Stout SM, Cimino NM. Exogenous cannabinoids as substrates, inhibitors, and inducers of human drug metabolizing enzymes: a systematic review. Drug Metab Rev. 2014;46:86-95.
- Zepatier (elbasvir; grazoprevir) tablet package insert. Whitehouse Station, NJ: Merck, Inc; 2016.
- Daklinza (daclatasvir) package insert. Princeton, NJ: Bristol-Myers Squibb Company; 2016.
- Viekira Pak (ombitasvir; paritaprevir; ritonavir; dasabuvir) tablet package insert. North Chicago, IL: AbbVie, Inc; 2016 Jun.
- Girennavar B, Jayaprakasha GK, and Patil BS. Potent inhibition of human cytochrome P450 3A4, 2D6, and 2C9 isoenzymes by grapefruit juice and its furocoumarins. Journal of Food Science. 2007;72(8):C417-C421.
- Harvoni (ledipasvir/sofosbuvir) package insert. Gilead Sciences, Inc. Foster City, CA 2014
- Copegus (ribavirin) package insert. Genentech, Inc. South San Francisco, CA, 2011
- Rebetol(ribavirin) package insert. Merc & Co Inc. Whitehouse Station, NJ 2013
- Solvadi (sofosbuvir)package insert. Gilead Sciences, Inc. Foster City, CA 2017
- Olysio (simeprevir) capsule package insert. Titusville, NJ: Janssen Therapeutics; 2016.
- Yamaori S, Ebisawa J, Okushima Y, Yamamoto I, Watanabe K. Potent inhibition of human cytochrome P450 3A isoforms by cannabidiol: Role of phenolic hydroxyl groups in the resorcinol moiety. Life Sciences. 2011;88:730-736.
- JIANG R, YAMAORI S, OKAMOTO Y, YAMAMOTO I, WATANABE K. Cannabidiol Is a Potent Inhibitor of the Catalytic Activity of Cytochrome P450 2C19. Drug Metabolism and Pharmacokinetics. 2013;28:332-338.
- Zhu H, Wang J, Markowitz JS, et al. Characterization of P-glycoprotein Inhibition by Major Cannabinoids from Marijuana. Journal of Pharmacology and Experimental Therapeutics. 2006;317:850-857.
- Dahan A, Altman H. Food-drug interaction: grapefruit juice augments drug bioavailability-mechanism, extent, and relevance. Eur J Clin Nutr 2004;58:1—9.